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Background: In mice models, eosinophils have been divided into different subpopulations with distinct phenotypes and functions, based on CD62L and CD101 patterns of membrane expression. Limited data are available in humans., Objective: To investigate eosinophils subpopulations in peripheral blood (PB) and nasal polyp tissue (NP) from severe eosinophilic asthma (SEA) patients plus concomitant chronic rhinosinusitis with nasal polyps (CRSwNP)., Methods: We recruited 23 SEA patients (14 with CRSwNP); as controls, we enrolled 15 non-severe asthma patients, 15 allergic rhinitis patients without asthma and 15 healthy donors. Eosinophils were isolated from PB and NP and analysed by FACS. Eotaxin-3 and eotaxin-1 mRNA expression in NP tissue was also evaluated., Results: A significantly higher percentage of circulating CD62L low cells was observed in SEA, as compared with controls, expressing higher levels of CCR3, CD69 and lower levels of CD125 (IL-5R), CRTH2, CD86 and CD28 in comparison with CD62L bright cells. In NP, eosinophils showed a high proportion of CD62L low phenotype, significantly greater than that observed in PB. Surface expression of IL-3R, IL-5R, CD69 and CD86 was significantly higher in CD62L low eosinophils from NP than in those from blood. Moreover, eotaxin-3 mRNA expression positively correlated with the percentage of CD62L low cells in NP., Conclusion: Two different eosinophil subphenotypes can be identified in blood and NP of SEA patients, with a preferential accumulation of CD62L low inflammatory cells in NP., (© 2022 John Wiley & Sons Ltd.)

Cystic fibrosis (CF) is the most common autosomal recessive disease among Caucasians. Over the last 20 years, culture-independent analysis, including next-generation sequencing, has paired with culture-based microbiology, offering deeper insight into CF lung and gut microbiota. The aim of this review is to analyse the features of gut microbiota in patients with CF and its possible role in the progression of the disease, establishing the basis for a potential role in microbe-based therapies. The literature analysis showed that the gut environment in CF patients has unique features due to the characteristics of the disease, such as decreased bicarbonate secretion, increased luminal viscosity, and an acidic small intestinal environment, which, due to the treatment, includes regular antibiotic use or a high-energy and fat-dense diet. As a result, the gut microbial composition appears altered, with reduced richness and diversity. Moreover, the population of pro-inflammatory bacteria is higher, while immunomodulatory genera, such as Bacteroides and Bifidobacterium , are scarcer. The imbalanced gut microbial population has a potential role in the development of systemic inflammation and may influence clinical outcomes, such as respiratory exacerbations, spirometry results, and overall growth. Although a better understanding of the pathophysiology behind the gut-lung axis is needed, these findings support the rationale for considering gut microbiota manipulation as a possible intervention to regulate the severity and progression of the disease.

Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of "overt" HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.

Study Objectives: To test the hypothesis that children taking trazodone have less leg movements during sleep (LMS) and higher rapid eye movement (REM) sleep atonia than children taking selective serotonin reuptake inhibitors (SSRIs) but more than normal controls., Methods: Fifteen children (9 girls and 6 boys, mean age 11.7 years, standard deviation [SD] 3.42) taking trazodone (median dosage 50 mg/d, range 25-200 mg) for insomnia and 19 children (11 girls and 8 boys, mean age 13.7 years, SD 3.07) taking SSRIs for depression, anxiety, or both were consecutively recruited, as well as an age- and sex-matched group of 25 control children (17 girls and 8 boys, mean age 13.7 years, SD 3.11). LMS were scored and a series of parameters was calculated, along with the analysis of their time structure. The Atonia Index was then computed for each non-REM sleep stage and for REM sleep., Results: Children taking trazodone exhibited slightly higher leg movement indices than controls but lower than those found in children taking SSRIs and their time structure was different. Chin electromyogram atonia in all sleep stages was not significantly altered in children taking trazodone but was decreased in children taking SSRIs, especially during non-REM sleep., Conclusions: In children, SSRIs but not trazodone are associated with a significantly increased number of LMS, including periodic LMS, and increased chin tone in all sleep stages. The assessment of periodic limb movement disorder and REM sleep without atonia might not be accurate when children are taking SSRIs because of their significant impact., Citation: DelRosso LM, Mogavero MP, Bruni O, Schenck CH, Fickenscher A, Ferri R. Trazodone affects periodic leg movements and chin muscle tone during sleep less than selective serotonin reuptake inhibitor antidepressants in children. J Clin Sleep Med . 2022;18(12):2829-2836., (© 2022 American Academy of Sleep Medicine.)

Respiratory tract infections (RTI) are mainly viral in origin and among the leading cause of childhood morbidity globally. Associated wheezing illness and asthma are still a clear unmet medical need. Despite the continuous progress in understanding the processes involved in their pathogenesis, preventive measures and treatments failed to demonstrate any significant disease-modifying effect. However, in the last decades it was understood that early-life exposure to microbes, may reduce the risk of infectious and allergic disorders, increasing the immune response efficacy. These results suggested that treatment with bacterial lysates (BLs) acting on gut microbiota, could promote a heterologous immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. This hypothesis has been supported by clinical and experimental studies showing the reduction of RTI frequency and severity in childhood after oral BL prophylaxis and elucidating the involved mechanisms. OM-85 is the product whose anti-viral effects have been most extensively studied in vitro , animal, and human cell studies and in translational animal infection/disease models. The results of the latter studies, describing the potential immune training-based activities of such BL, leading to the protection against respiratory viruses, will be reported. In response to human rhinovirus, influenza virus, respiratory syncytial virus and severe acute respiratory coronavirus-2 , OM-85 was effective in modulating the structure and the functions of a large numbers of airways epithelial and immune cells, when administered both orally and intranasally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Ballarini, Ardusso, Ortega Martell, Sacco, Feleszko and Rossi.)

Testudo hermanni is included as near‑threatened in the Red List of the International Union for Conservation of Nature, while T. hermanni hermanni is considered endangered in the Italian Red List. Appropriate management of smuggled or seized wild individuals is recommended before their reintroduction into the wild. Accordingly, a health monitoring study was carried out. During 2014‑2016, 133 oral swabs and 121 cloacal swabs were collected from a total of approximately 180 free‑ranging and rescued T. hermanni hermanni from eight different Italian regions to investigate the presence of DNA of Testudinid alphaherpesvirus (TeAHV), Chlamydia spp. and Mycoplasma spp. in the oral cavity, and Salmonella spp. isolates in the cloaca. Mycoplasma spp. was detected in 52 out of 87 (59.77%) of rescued and in 1 out of 46 free‑ranging (2.17%) individuals; 33 out of 53 (62.26%) Mycoplasma spp. positive samples were typed as M. agassizii by PCR. Salmonella spp. was isolated from 45 out of 121 (37.19%) cloacal swabs, typed into 14 serovars, and characterized for complete antimicrobial susceptibility. A significantly different distribution of Salmonella spp. isolates was found in 2016 in comparison with 2014 and 2015, without any difference between free‑ranging and rescued tortoises. All the tested tortoises were negative for TeAHV and Chlamydia spp. These results are considered a baseline information critical to monitor the dynamics of these microorganisms in free‑ranging and rescued populations of T. h. hermanni, and to correctly approach the management of rescued animals and possible relocation programs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

Background: Hotspots of intraspecific genetic diversity represent invaluable resources for species to cope with environmental changes, and their identification is increasingly recognized as a major goal of conservation ecology research. However, even for iconic and endangered species, conservation strategies are often planned without thorough information on the geographic patterns of genetic variation. Here, we investigated the spatial patterns of genetic variation of the endangered Hermann's tortoise Testudo hermanni in the Italian Peninsula by genotyping 174 individuals at 7 microsatellite loci, with the aim to contribute to planning effective conservation strategies., Results: Ordination-based and Bayesian clustering analyses consistently identified three main genetic clusters, one spread in the central and northern part of the peninsula, and two restricted to southern Italy and Sicily, respectively. The highest levels of genetic diversity were found in populations of the southern cluster and, in particular, at the northern edges of its distribution (He > 0.6, Ar > 2.8 ), that correspond to areas of putative secondary contact and admixture between distinct lineages. Our results clearly identify a hotspot of genetic diversity for the Hermann's tortoise in southern Italy., Conclusion: We inferred the evolutionary history and the spatial patterns of genetic variation of the Hermann's tortoise in the Italian Peninsula. We identified three main genetic clusters along the peninsula and a hotspot of intraspecific diversity in southern Italy. Our results underline the urgent need for conservation actions to warrant the long-term persistence of viable tortoise populations in this area. Furthrmore, these data add further evidence to the role of southern Italy as a biodiversity hotspot for temperate fauna, claiming for higher consideration of this area in large scale conservation programs., (© 2022. The Author(s).)

IgE-mediated diseases represent a highly diversified and multifactorial group of disorders that can deeply impact the patients' quality of life. Currently, allergy immunotherapy (AIT) still remains the gold standard for the management of such pathologies. In this review, we comprehensively examine and discuss how AIT can affect both the innate and the adaptive immune responses at different cell levels and propose timing-scheduled alterations induced by AIT by hypothesizing five sequential phases: after the desensitization of effector non-lymphoid cells and a transient increase of IgE (phase 1), high doses of allergen given by AIT stimulate the shift from type 2/type 3 towards type 1 response (phase 2), which is progressively potentiated by the increase of IFN-γ that promotes the chronic activation of APCs, progressively leading to the hyperexpression of Notch1L (Delta4) and the secretion of IL-12 and IL-27, which are essential to activate IL-10 gene in Th1 and ILC1 cells. As consequence, an expansion of circulating memory Th1/Tr1 cells and ILC-reg characterizes the third phase addressed to antagonize/balance the excess of type 1 response (phase 3). The progressive increase of IL-10 triggers a number of regulatory circuits sustained by innate and adaptive immune cells and favoring T-cell tolerance (phase 4), which may also be maintained for a long period after AIT interruption (phase 5). Different administration approaches of AIT have shown a similar tailoring of the immune responses and can be monitored by timely, optimized biomarkers. The clinical failure of this treatment can occur, and many genetic/epigenetic polymorphisms/mutations involving several immunological mechanisms, such as the plasticity of immune responses and the induction/maintenance of regulatory circuits, have been described. The knowledge of how AIT can shape the immune system and its responses is a key tool to develop novel AIT strategies including the engineering of allergen or their epitopes. We now have the potential to understand the precise causes of AIT failure and to establish the best biomarkers of AIT efficacy in each phase of the treatment.

Background: Antibiotic stewardship (AS) is a cornerstone of the fight against antimicrobial resistance; however, evidence on the best practice to improve antibiotic prescription in various hospital settings is still scarce. This study aimed to measure the efficacy of a non-restrictive AS intervention in the internal medicine area of a tertiary-care hospital across a 3-year period., Methods: The intervention comprised a 3-month 'intensive phase' based on education and guidelines provision, followed by 9 months of audits and feedback activities. The primary outcome was the overall antibiotic consumption measured as days of therapy (DOTs) and defined daily doses (DDDs). Secondary outcomes were carbapenem and fluoroquinolone consumption, all-cause in-hospital mortality, length of stay, incidence of Clostridioides difficile and carbapenem-resistant Enterobacterales bloodstream infections (CRE-BSIs). All outcomes were measured in the intervention wards comparing the pre-phase with the post-phase using an interrupted time-series model., Results: A total of 145 337 patient days (PDs) and 14 159 admissions were included in the analysis. The intervention was associated with reduced DOTs*1000PDs (-162.2/P = 0.005) and DDDs*1000PDs (-183.6/P ≤ 0.001). A sustained decrease in ward-related antibiotic consumption was also detected during the post-intervention phase and in the carbapenem/fluoroquinolone classes. The intervention was associated with an immediate reduction in length of stay (-1.72 days/P < 0.001) and all-cause mortality (-3.71 deaths*100 admissions/P = 0.002), with a decreasing trend over time. Rates of Clostridioides difficile infections and CRE-BSIs were not significantly impacted by the intervention., Conclusions: The AS intervention was effective and safe in decreasing antibiotic consumption and length of stay in the internal medicine area. Enabling prescribers to judicious use of antimicrobials through active participation in AS initiatives is key to reach sustained results over time., (Copyright © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Endothelin-1 (ET-1) is a vasoactive and profibrotic peptide that plays a pivotal role in diseases such as systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), by inducing fibrosis and vascular remodeling. Such effects may be sustained by the induction of aldosterone production and reactive oxygen species (ROS). We have used fibroblasts obtained from skin of healthy donors and SSc patients and commercial fibroblasts from lung to evaluate whether ET-1 is able to stimulate ROS production directly or indirectly through aldosterone induction. We found that ET-1 receptors are present in all types of fibroblasts analyzed, whereas the expression of mineralocorticoid receptor (MCR) is lower in dermal fibroblasts from healthy donors (HDFs) compared to fibroblasts derived from lung (HPFs) or from skin of SSc patients (SScHDFs). ET-1 induces ROS production in HDFs and SScHDFs after 24 h of incubation involving its receptor B (ETB), whereas aldosterone exerts its effects after 40 min of incubation. Moreover, ROS production was inhibited by the pre-incubation of cells with MCR inhibitor. Our results indicate that ET-1 induces ROS indirectly through aldosterone production suggesting that aldosterone may play a pivotal role in the pathogenesis of SSc and PAH.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-vessel necrotizing vasculitis with multiple organ involvement. Despite improvements in clinical management, biomarkers for organ involvement and disease prognosis are still an unmet need. Methods: EGPA patients referred to our immunology clinic were retrospectively reviewed. Demographic/clinical features, eosinophils, ANCA status, eosinophil cationic protein (ECP) and total serum IgE were evaluated at the baseline. Eosinophils, total serum IgE, ECP and ANCA were studied as possible biomarkers for lung and extrapulmonary disease. Results: In total, 167 EGPA patients were recruited for our study. A positive association between eosinophils and peripheral nervous system (PNS) involvement was demonstrated (p <0.001; chi-squared test). Receiver operating characteristic (ROC) curves using the eosinophil count or percentage as predictors of PNS involvement yielded AUC values of 0.75 and 0.67, respectively. ANCA positivity was associated with PNS involvement, while no correlations with clinical parameters were found for ECP and total serum IgE. Patients without extrapulmonary involvement had lower eosinophils (eosinophils: 2844.7 ± 1698 vs. 6373 ± 5468, p < 0.001; eosinophil percentage: 24.6 ± 10% vs. 36.2 ± 15.8, p < 0.001) and were less likely to be ANCA+ (p < 0.001, chi-squared test). Conclusion: Eosinophils in EGPA are an important biomarker and are associated with extrapulmonary involvement. These findings could strengthen the role of anti-eosinophilic drugs in improving extrapulmonary disease.

The introduction of an electron-donating triphenylamine motive into a 2,2',6',2''-terpyridine (terpy) moiety, a cornerstone molecular unit in coordination chemistry, opens new ways for a rational design of photophysical properties of organic and inorganic compounds. A push-pull compound, 4'-(4-(di(4-tert-butylphenyl)amine)phenyl)-2,2',6',2''-terpyridine (tBuTPAterpy), was thoroughly investigated with the use of steady-state and time-resolved spectroscopies and Density Functional Theory (DFT) calculations. Our results demonstrate that solvent parameters have an enormous influence on the optical properties of this molecule, acting as knobs for external control of its photophysics. The Intramolecular Charge Transfer (ICT) process introduces a remarkable solvent polarity effect on the emission spectra without affecting the lowest absorption band, as confirmed by DFT simulations, including solvation effects. The calculations ascribe the lowest absorption transitions to two singlet ICT excited states, S 1 and S 2 , with S 1 having several orders of magnitude higher oscillator strength than the "dark" S 2 state. Temperature and viscosity investigations suggest the existence of two emitting excited states with different structural conformations. The phosphorescence emission band observed at 77 K is assigned to a localized 3 terpy state. Finally, protonation studies show that tBuTPAterpy undergoes a reversible process, making it a promising probe of the pH level in the context of acidity determination.

Background: Children with Attention-Deficit/Hyperactivity (ADHD) and/or Developmental Coordination Disorder (DCD) show high rates of motor difficulties in daily activities. This study aimed to examine the validity and reliability of the Developmental Coordination Disorder Questionnaire (DCDQ) in identifying motor characteristics in daily activities, differentiating children with ADHD-only, with DCD-only and with ADHD and DCD comorbidity., Methods: Thirty-three children with ADHD-only, 30 with DCD-only, 33 with ADHD/DCD, and 35 controls participated to the study. Diagnosis satisfied DSM-5 criteria for ADHD and DCD. The DCDQ was administered to all children; moreover, the association between DCDQ scores and ADHD symptoms, measured by SNAP-IV, and motor coordination severity, measured by M-ABC subscales, was examined., Results: The DCDQ subscale scores were significantly lower in all clinical groups than in controls, but only minimal differences were found between the clinical groups. Principal Component Analysis (PCA) of DCDQ identified five components showing the best adaptability and accounting for 71% of the variance. Both ADHD-only and ADHD/DCD achieved a better performance than DCD-only in the "Motor control in running/jumping". Conversely, children with DCD-only performed better in "General coordination". ADHD-only reached better mean scores than ADHD/DCD in "Motor control with the ball" and, than DCD, in "Planning". Inattention, hyperactivity-impulsivity at SNAP-IV, and balance at M-ABC, represented the main predictors for ADHD-only, ADHD/DCD and DCD-only, respectively., Conclusions: DCDQ may represent a useful measure to detect the different areas of difficulties in children with neurodevelopmental disorders and provides suggestions for identifying distinct altered processes underlying ADHD and DCD, alone or in comorbidity.

Objective: To review, critically analyze and synthesize knowledge from the international literature regarding the association between allergic rhinitis (AR) and sleep disorders, the impact of AR treatment on children's sleep, and lay the foundation for future research on this topic., Source of Data: A literature search using PubMed database including original and review articles, systematic reviews and meta-analyses using keywords related to AR, sleep disorders and sleep-disordered breathing., Synthesis of Data: Sleep is fundamental to health, and its assessment and control of conditions that trigger or aggravate disturbances are of the uttermost importance. Allergic rhinitis (AR) is common in children and may interfere with both their quality of life and quality of sleep. It has emerged as one of the most important risk factors for habitual snoring in children and appeared to increase the risk of Obstructive Sleep Apnea (OSA), with AR severity exhibiting a significant and independent association with pediatric OSA severity. However, in some studies, those associations between AR and OSA in children are not very consistent., Conclusions: A substantial level of controversy exists regarding the interactions between AR and OSA in children. Notwithstanding, identifying and treating AR in clinical settings is probably an important step toward improving symptoms and preventing deterioration of sleep quality in children and may improve the severity of underlying OSA. Considering the high prevalence, morbidity, economic and social implications of both AR and sleep problems, it is crucial that healthcare providers improve their understanding of the relationships between those conditions among children., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: Pediatric headaches have been linked to adverse life events or psychological factors in children and their families, with a complex and bidirectional association. Moreover, it is well-known that psychological stress can trigger headaches., Methods: We searched three databases for studies focusing on headaches and adverse events or psychological factors in children up to 12 years old or in their caregivers., Results: We included 28 studies. Child psychological factors, including internal and external symptoms, were commonly associated with all types of headaches. Sleep disturbances showed a positive association with headaches in 3 out of 5 studies. Family conflict and unhappiness were frequently found in children suffering with headaches, while single-parent families and divorce were not associated. Stressful environments and adverse life events, particularly bullying, were also found to be linked with headaches., Conclusions: Childhood headaches represent an alarm bell for clinicians to investigate and treat psychological or psychiatric disorders in children and their family. Further studies are needed to elucidate the role of early-life adverse events in children and their families., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose of Review: In this review we summarized the available evidence on sleep disorders in children with neurodevelopmental disorders (NDDs) in particular: intellectual disability (including some genetic conditions such as Prader-Willi Syndrome, Smith-Magenis Syndrome), Autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), Developmental Coordination Disorder, language disorders, and specific learning disorders., Recent Findings: Children with NDDs frequently suffer from sleep disturbances, with a higher prevalence than that of the general pediatric population., Summary: These problems tend to be chronic and may cause additional cognitive and behavioral difficulties, often affecting the whole family's well-being. Sleep behaviors are also related to other important developmental skills, such as attention and listening. Investigating sleep disorders in children with NDDs is therefore crucial in clinical practice. For a systematic approach in clinical practice, we propose the use of a short and easy to remember sleep screening tool., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction/aim: Muscle alterations, portosystemic shunts (SPSS) and minimal hepatic encephalopathy (MHE) are related to hepatic encephalopathy (HE), however no studies have investigated the relative role of all these risk factors detected in the same patients. The aim of the study was to assess the prognostic impact of muscle alterations, MHE and SPSS on hepatic encephalopathy and transplant free survival., Patients/methods: 114 cirrhotics were submitted to Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT) to detect MHE. CT scan was used to analyze the skeletal muscle index (SMI), muscle attenuation and SPSS. The incidence of the first episode of HE and survival were estimated., Results: Previous HE was present in 47 patients (41%). The variables independently associated to previous HE were: sarcopenia, MHE and SPSS. 44 patients (39%) developed overt HE during 14±11 months; MHE and SPSS were the only variables significantly asociated to overt HE. During the same follow-up, 42 patients died (37%); MELD and sarcopenia were the only variables significantly asociated to transplant free survival., Conclusions: MHE, sarcopenia and SPSS are clinically relevant and should be sought for in cirrhotics. In particular, MHE and SPSS are the only risk factors significantly associated to the development of HE while MELD and sarcopenia are independently associated to overall mortality., Competing Interests: Conflict of interest None declared., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: This study sought to describe patient characteristics and treatment patterns among patients with insomnia prescribed trazodone in the United States., Methods: This real-world, retrospective, descriptive cohort study used US commercial insurance claims from July 1, 2009, through June 30, 2019. The index date was the first prescription for trazodone between January 1, 2010, and December 31, 2018, with 6 months for the preindex period and ≥6 months for the postindex period., Findings: Among 5.8 million patients with insomnia, 17.7% were prescribed trazodone, and 357,380 adults (6.2%) and 7564 children (0.1%) met the study eligibility criteria. The mean (SD) age was 48.8 (15.8) years for adults and 14.8 (2.7) years for pediatrics. Most patients were female (229,280 adults [64.2%] and 4481 children [59.2%]). Insomnia due to mental disorder was the most common specific diagnosis. The most common (>25%) comorbid conditions were anxiety, depression, and hypertensive disease, and 1 of 10 had a history of substance abuse. Zolpidem was previously prescribed (73,342 adults [20.5%] and 233 children [3.1%]) and continued to be prescribed. Concomitant antidepressants were most common (216,893 adults [60.7%] and 5414 children [71.6%]), but benzodiazepines (132,740 adults [37.1%] and 1188 children [15.7%]), antiepileptics (115,064 adults [32.2%] and 2103 children [27.8%]), nonbenzodiazepines (90,946 adults [25.4%] and 542 children [7.2%]), and antipsychotics (40,490 adults [11.3%] and 2063 children [27.3%]) were also prescribed., Implications: This study provides current evidence that trazodone use is widespread among patients with insomnia and is often associated with other specific comorbidities, such as psychiatric conditions. A deeper knowledge of the real-world management of patients with insomnia may facilitate steps toward improving sleep quality, daytime functioning, and clinical outcomes for patients., Competing Interests: Declaration of Competing Interest All authors have seen and approved the manuscript. This study was sponsored by Angelini Pharma S.p.A., of which I. Pochiero, M. Gorini, A. Comandini, F. Calisti, G. Di Loreto, and A. Cattaneo are employees. The study was conducted by Labcorp Drug Development, of which T. Knight, K.P. Anastassopoulos, R. Patel, and R. Baik are employees. O. Bruni is a consultant for Fidia Pharma., (Copyright © 2022. Published by Elsevier Inc.)

Between 50-80% of children with autism spectrum disorder (ASD) have insomnia, which adversely affects their mental and physical health. However, there is no consensus to-date on suitable tools for insomnia screening and monitoring in daily clinical practice. An expert panel of child neuropsychiatry and sleep specialists, with expertise in children with neurodevelopmental disabilities, recommends: (1) performing insomnia screening of all children with ASD; (2) considering discussion or referral to a sleep specialist when comorbid sleep disorders are suspected. The panel further developed structured, brief screening and monitoring tools to facilitate insomnia screening and management in daily practice, monitor treatment effectiveness and standardize and compare outcomes across clinical settings to improve care and well-being of children with ASD and their families., (© 2021. The Author(s).)

Sleep terrors (STs) are sleep disorders characterized by abrupt arousal from sleep with autonomic hyperactivity and inappropriate behavior. Though a common condition in childhood that usually affects children between 4 and 12 years of age, STs, however, may be present even in adulthood. The exact etiology of STs is not known yet, however, several hypotheses have been proposed over the years, identifying some potential genetic, neurodevelopmental, or other causes. Nevertheless, a useful pathophysiological model identified a common cascade of predisposing, priming, and precipitating factors, which could help to explain and sometimes prevent STs. Establishing a correct diagnosis is mandatory for appropriate management, as several conditions (such as other parasomnias or nocturnal seizures) may mimic STs. Furthermore, we also described some conditions which can be comorbid to STs, like some medical or psychological disorders. A number of treatment options have been proposed, ranging from only sleep hygiene practices to pharmacological therapies; we reviewed some of the most prominent ones. In spite of the fact that STs have long been considered benign disorders, which tend to reduce spontaneously over the years, they may have unexpected consequences on the child but also on the caregivers., (© 2021 Wiley Periodicals LLC.)

The European Somnologist certification programme was developed by the European Sleep Research Society to improve patient care in sleep medicine by providing an independent evaluation of theoretical and practical knowledge. The examination of eligible experts plays a key role in this procedure. A process was started more than 15 years ago to create the European sleep medicine curriculum, eligibility criteria for certification, and sleep centre accreditation criteria. The process was characterised by interdisciplinary collaboration, consensus, and achieving new solutions. During the past 10 years, experience has been gained by the examination and certification of more than 1000 sleep medicine experts from more than 50 countries. The process has continuously been improved. However, as the programme was designed and administered mainly by medical experts in the field, systematic influence from teaching and pedagogic experts was partially underrepresented. The current critical appraisal pinpoints several missing links in the process - mainly as a missing constructive alignment between learning objectives, learning and teaching activities, and the final assessment. A series of suggestions has been made to further improve the ESRS certification programme., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Among brain cancers, glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high cell heterogeneity, which can be linked to its high malignancy. We have previously demonstrated that TRPML1 channels affect the OS of GBM patients. Herein, by RT-PCR, FACS and Western blot, we demonstrated that TRPML1 and TRPML2 channels are differently expressed in GBM patients and cell lines. Moreover, these channels partially colocalized in ER and lysosomal compartments in GBM cell lines, as evaluated by confocal analysis. Interestingly, the silencing of TRPML1 or TRPML2 by RNA interference results in the decrease in the other receptor at protein level. Moreover, the double knockdown of TRPML1 and TRPML2 leads to increased GBM cell survival with respect to single-channel-silenced cells, and improves migration and invasion ability of U251 cells. Finally, the Kaplan-Meier survival analysis demonstrated that patients with high TRPML2 expression in absence of TRPML1 expression strongly correlates with short OS, whereas high TRPML1 associated with low TRPML2 mRNA expression correlates with longer OS in GBM patients. The worst OS in GBM patients is associated with the loss of both TRPML1 and TRPML2 channels.

Purpose of Review: Restless sleep disorder (RSD) is a recently identified pediatric sleep disorder characterized by frequent movements during sleep associated with daytime symptoms. In this review we summarize the expanding evidence of the clinical presentation of RSD, potential pathophysiology, associated comorbidities, and current treatment options that will help the pediatrician identify children with RSD in a timely manner., Recent Findings: RSD is diagnosed in 7.7% of children referred evaluated in a pediatric sleep center. Children with RSD present with frequent nightly movements during sleep for at least 3 months, and have daytime symptoms related to poor sleep quality including excessive sleepiness, hyperactivity, irritability among other symptoms. Current evidence shows an increased sympathetic predominance, increased NREM sleep instability, and iron deficiency, as well as increased prevalence in parasomnias and attention deficit hyperactivity disorder. Consensus diagnostic criteria were recently published to diagnose RSD and emergent evidence suggests that iron supplementation improves its nighttime and daytime symptoms., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

About 5% of the disulfide bonds (DBs) observed in the Protein Data Bank bridge two protein chains. Several of their features were comprehensively analyzed, resulting in a structural atlas of the intermolecular DBs. The analysis was performed on a very large set of data extracted from the Protein Data Bank, according to the RaSPDB procedure. It was observed that the two chains tend to have different sequences and belong to the same structural class. Intermolecular DBs tend to be more solvent accessible and less distorted from the most stable conformation than intermolecular DBs while showing similar B-factors. They tend to occur in beta strands and in mainly-beta structures. These and other data should prove useful in protein modelling and design.

Background and Aims: Genetic testing is still rarely used for the diagnosis of dyslipidemia, even though gene variants determining plasma lipids levels are not uncommon., Methods: Starting from a a pilot-analysis of targeted Next Generation Sequencing (NGS) of 5 genes related to familial hypercholesterolemia ( LDLR , APOB , PCSK9 , HMGCR , APOE ) within a cardiovascular cohort in subjects with extreme plasma concentrations of low-density lipoprotein (LDL) cholesterol, we discovered and characterized a novel point mutation in the APOB gene, which was associated with very low levels of apolipoprotein B (ApoB) and LDL cholesterol., Results: APOB c.6943 G > T induces a premature stop codon at the level of exon 26 in the APOB gene and generates a protein which has the 51% of the mass of the wild type ApoB-100 (ApoB-51), with a truncation at the level of residue 2315. The premature stop codon occurs after the one needed for the synthesis of ApoB-48, allowing chylomicron production at intestinal level and thus avoiding potential nutritional impairments. The heterozygous carrier of APOB c.6943G > T, despite a very high-risk profile encompassing all the traditional risk factors except for dyslipidemia, had normal coronary arteries by angiography and did not report any major adverse cardiovascular event during a 20-years follow-up, thereby obtaining advantage from the gene variant as regards protection against atherosclerosis, apparently without any metabolic retaliation., Conclusions: Our data support the use of targeted NGS in well-characterized clinical settings, as well as they indicate that.a partial block of ApoB production may be well tolerated and improve cardiovascular outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Chemical characterization of the bulbs of Drimia pancration was conducted to isolate four steroidal saponins ( 1 - 4 ). Earlier, we focused on the structural elucidation of compounds 1 - 3 . Herein, by means of 1 H-NMR, 13 C-NMR, Nuclear Overhauser Effects (NOE), and 2D-NMR spectra, the full stereochemical structure of 4 is reported, and all the 1 H and 13 C signals are assigned. Compounds 1 - 4 were tested for their acaricidal properties against the two-spotted spider mite Tetranychus urticae . Our results showed excellent activity of compound 1, with an LD 50 (µg/cm 2 ) of 0.29 and a LD 90 (µg/cm 2 ) of 0.96, whereas compounds 2 , 3 , and 4 showed moderate activity. Furthermore, the acaricidal and cytotoxic properties of the crude extract were also investigated. Of note, after 96 h of exposure, the acaricidal activity of compound 1 was higher than that of the positive control, hexythiazox. Indeed, for compound 1 , LD 50 and LD 90 were 0.29 and 0.96 µg/cm 2 , respectively, while hexythiazox LD 50(90) was 18.7 (132.5) µg/cm 2 . Additionally, D. pancration extract, after 72 h, induced a high cytotoxic effect in HaCaT and THP-1 cell lines, with an IC 50 of 7.37 ± 0.5 µg/mL and 3.50 ± 0.15 µg/mL, respectively. Overall, D. pancration can be considered as a green source of novel acaricides effective against mites of agricultural importance, such as T. urticae , pending proper field validation and the assessment of non-target effects on other invertebrate species.

Lockdown experience for COVID-19 pandemic significantly affected children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD) exacerbating or promoting the onset of externalizing and internalizing symptoms. However, few studies have considered how externalizing and internalizing behaviors changed in relation to parental emotions and parenting strategies. In the present study, 992 caregivers of children and adolescents with ADHD from 5 to 18 years were presented with an online survey evaluating youths' externalizing and internalizing behaviors, their non-compliance with lockdown rules, and parental factors related to parental emotions and parenting strategies. Two hierarchical linear regression models were performed to examine the contribution of children's non-compliance with lockdown rules, parental emotions, and parenting strategies on children's externalizing and internalizing behaviors. Results revealed that externalizing behaviors were higher in children and adolescents with ADHD non-compliant with lockdown rules. Moreover, positive parenting strategies moderated the relationship between non-compliance with lockdown rules and externalizing behaviors. Differently, higher internalizing behaviors were observed in children with ADHD who had parents reporting more negative emotions and positive parenting strategies. In this case, parents' negative emotions had a moderator effect in the association between internalizing behaviors and non-compliance to lockdown measures. The clinical implications of these two different patterns of relations are discussed.

This paper aims to review the limitations of the current classification of insomnia of early childhood and propose a new conceptual model allowing a better understanding of its pathophysiology. Our hypothesis is that chronic insomnia of childhood has different phenotypical expressions, associated to different pathophysiological mechanisms. Based on a long-lasting experience in evaluating a very large number of children with specific insomnia symptoms (nocturnal awakenings, difficulty in falling asleep, nocturnal restlessness, early morning awakenings) and on published data, we hypothesize that different phenotypes of insomnia might exist with different therapeutic implications. We describe three phenotypes of insomnia in early childhood: a) insomnia with motor restlessness; b) insomnia characterized without difficulties in falling asleep but with long-lasting early morning awakenings; c) insomnia with multiple night awakenings and falling asleep difficulty. This type of categorization might have important implications for treatment, based on the different hypothetical neurotransmitter dysfunctions. The early identification of a phenotype of insomnia might guide to specific behavioral and/or pharmacological interventions with the aim to prevent chronic insomnia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The coronavirus disease (COVID-19) pandemic represented an unprecedented challenge for health care facilities, and innovative solutions were urgently required to overcome the high volume of critically ill infectious patients, limit in-hospital outbreaks, and limit the risk of occupational infection for health care workers (HCWs). Bergamo was the hardest-hit Italian province by COVID-19, and the local health care system had to undergo a profound and prompt reorganization. A COVID-19-only field hospital was rapidly set up meeting the standards for severe acute respiratory infection (SARI) treatment centers (https://apps.who.int/iris/handle/10665/331603). A zones partition, dedicated in-hospital pathways for HCWs, strict infection prevention and control (IPC) measures, and constant staff supervision were key components of our strategy to limit the risk of occupational infection for HCWs. Herein, we present the Bergamo field hospital layout enlightening fundamental IPC measures adopted as a valuable example of a SARI treatment center confronting COVID-19.

Severe respiratory syncytial virus (RSV) infection in infancy is associated with increased risk of recurrent wheezing in childhood. Both acute and long-term alterations in airway functions are thought to be related to inefficient antiviral immune response. The airway epithelium, the first target of RSV, normally acts as an immunological barrier able to elicit an effective immune reaction but may also be programmed to directly promote a Th2 response, independently from Th2 lymphocyte involvement. Recognition of RSV transcripts and viral replication intermediates by bronchial epithelial cells brings about release of TSLP, IL-33, HMGB1, and IL-25, dubbed "alarmins." These epithelial cell-derived proteins are particularly effective in stimulating innate lymphoid cells 2 (ILC2) to release IL-4, IL-5, and IL-13. ILC2, reflect the innate counterparts of Th2 cells and, when activate, are potent promoters of airway inflammation and hyperresponsiveness in RSV bronchiolitis and childhood wheezing/asthma. Long-term epithelial progenitors or persistent epigenetic modifications of the airway epithelium following RSV infection may play a pathogenetic role in the short- and long-term increased susceptibility to obstructive lung diseases in response to RSV in the young. Additionally, ILC2 function may be further regulated by RSV-induced changes in gut microbiota community composition that can be associated with disease severity in infants. A better understanding of the alarmin-ILC interactions in childhood might provide insights into the mechanisms characterizing these immune-mediated diseases and indicate new targets for prevention and therapeutic interventions., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The blockade of the PD-L1/PD-1 immune checkpoint has promising efficacy in cancer treatment. However, few patients with bladder cancer (BC) or renal cell carcinoma (RCC) respond to this approach. Thus, it is important to implement a strategy to stimulate the immune anti-tumor response. In this scenario, our study evaluated the effects of a low capsaicin (CPS) dose in BC and RCC cell lines. Western blot, qRT-PCR and confocal microscopy were used to assess PD-L1 mRNA and protein expression. Alterations to the cellular oxidative status and changes to the antioxidant NME4 levels, mRNA modulation of cytokines, growth factors, transcriptional factors and oncogene, and the activation of Stat1/Stat3 pathways were examined using Western blot, cytofluorimetry and qRT-PCR profiling assays. In BC, CPS triggers an altered stress oxidative-mediated DNA double-strand break response and increases the PD-L1 expression. On the contrary, in RCC, CPS, by stimulating an efficient DNA damage repair response, thus triggering protein carbonylation, reduces the PD-L1 expression. Overall, our results show that CPS mediates a multi-faceted approach. In modulating PD-L1 expression, there is a rationale for CPS exploitation as a stimulus that increases BC cells' response to immunotherapy or as an immune adjuvant to improve the efficacy of the conventional therapy in RCC patients.

Background: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions., Methods: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA)., Results: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated., Conclusions: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect., (© 2022. The Author(s).)

Hepatic encephalopathy (HE) represents a common complication of liver cirrhosis. Protein-calorie malnutrition is frequently encountered in the cirrhotic patient and its most obvious clinical manifestation is sarcopenia. This condition represents a risk factor for HE occurrence because skeletal muscle acts as an alternative site for ammonium detoxification. Preventive intervention through an adequate assessment of nutritional status should be carried out at early stages of the disease and in a multidisciplinary team using both non-instrumental methods (food diary, anthropometric measurements, blood chemistry tests) and instrumental methods (bioimpedance testing, DEXA, CT, indirect calorimetry, dynamometry). Dietary recommendations for patients with HE do not differ from those for cirrhotic patient without HE. Daily caloric intake in the non-obese patient should be 30-40 Kcal/Kg/day with a protein intake of 1-1.5 g/Kg/day, especially of vegetable origin, through 4-6 meals daily. In patients with HE, it is also essential to monitor electrolyte balance, supplementing any micronutrient deficiencies such as sodium and zinc, as well as vitamin deficiencies because they can cause neurological symptoms similar to those of HE. In light of the critical role of nutritional status, this aspect should not be underestimated and should be included in the diagnostic-therapeutic algorithm of patients with HE.

Background: Orphan drugs are used for the diagnosis, prevention and treatment of rare diseases that, in the European Union, are defined as disorders affecting no more than 5 persons in 10,000. So far, a total of around 800 orphan medicinal products have been approved by the European Medicines Agency, however the utilization profile of orphan drugs has yet to be explored. This study aimed at assessing the utilization profile of orphan drugs authorized for marketing by the Italian Medicines Agency using population-based data. Methods: A total of 21 orphan drugs used in outpatient settings, approved in the European Union before or during the 2008-2018 period and involving 15 rare diseases, were included in the study. The monitored population included patients with one of the conditions surveilled by the population-based Tuscany Registry of Rare Diseases and diagnosed between 2000-2018. A multi-database approach was applied, by linking data from the registry with information collected in drug prescriptions databases. The prevalence and intensity of use were estimated for the selected orphan drugs and other non-orphan medications, used to treat the same rare disease and for which a change in the prevalence of use was hypothesized after authorization of the orphan drug. Results: For some diseases (acquired aplastic anemia, tuberous sclerosis complex, most metabolic diseases) a low prevalence of orphan drugs use was observed (range between 1.1-12.5%). Conversely, orphan drugs were frequently used in hemophilia B, Wilson disease and idiopathic pulmonary fibrosis (maximum of 78.3, 47.6 and 41.8%, respectively). For hemophilia B and Leber's hereditary optic neuropathy, there are currently no other medications used in clinical practice in addition to orphan drugs. Six orphan drugs were used for the treatment of pulmonary arterial hypertension, appearing the elective therapy for this disease, albeit with different utilization profiles (range of prevalence 1.7-55.6%). Conclusion: To the best of our knowledge, this is the first study investigating the utilization profile of orphan drugs prescribed in a defined geographical area, and providing relevant information to monitor over time potential changes in the prevalence of these medications as well as in the health care decision making., Competing Interests: RG reports a relationship with Tuscany Region that includes: funding grants. RG reports a relationship with Fondazione Cassa di Risparmio di Firenze that includes: funding grants. RG reports a relationship with Italian Ministry of Health that includes: funding grants. RG reports a relationship with Zogenix that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. RG reports a relationship with Biocodex that includes: speaking and lecture fees and travel reimbursement. PC reports a relationship with GSK SRL that includes: speaking and lecture fees. PC reports a relationship with AstraZeneca SpA that includes: speaking and lecture fees. GC reports a relationship with SOBI that includes: funding grants. GC reports a relationship with CSL Behring Spa that includes: funding grants. GC reports a relationship with Roche that includes: board membership, consulting or advisory, and speaking and lecture fees. GC reports a relationship with Bayer that includes: board membership and speaking and lecture fees. GC reports a relationship with CSL Berhing that includes: board membership and speaking and lecture fees. GC reports a relationship with Biomarin that includes: board membership and speaking and lecture fees. GC reports a relationship with Sanofi that includes: board membership and speaking and lecture fees. GC reports a relationship with Novo Nordisk that includes: board membership and speaking and lecture fees. GC reports a relationship with Takeda that includes: board membership and speaking and lecture fees. GC reports a relationship with Kedrion that includes: board membership and speaking and lecture fees. GC reports a relationship with LFB that includes: board membership and speaking and lecture fees. GC reports a relationship with Grifols that includes: board membership and speaking and lecture fees. GC reports a relationship with UniQure Inc. that includes: board membership and speaking and lecture fees. PP reports a relationship with GSK that includes: speaking and lecture fees. PP reports a relationship with LEOPharma that includes: speaking and lecture fees. FC reports a relationship with Pfizer that includes: consulting or advisory. FC reports a relationship with Alnylam that includes: consulting or advisory. FC reports a relationship with Akcea that includes: consulting or advisory. BS reports a relationship with Jazz that includes: speaking and lecture fees. BS reports a relationship with Pfizer that includes: board membership and speaking and lecture fees. BS reports a relationship with Novartis that includes: speaking and lecture fees. BS reports a relationship with Ariad that includes: speaking and lecture fees. BS reports a relationship with Amgen that includes: board membership and travel reimbursement. BS reports a relationship with Sanofi that includes: travel reimbursement. IO reports a relationship with Amicus that includes: consulting or advisory and funding grants. IO reports a relationship with Genzyme that includes: consulting or advisory and funding grants. IO reports a relationship with Menarini International that includes: funding grants. IO reports a relationship with BMS that includes: board membership, consulting or advisory, and funding grants. IO reports a relationship with Cytokinetics Inc. that includes: board membership, consulting or advisory, and funding grants. IO reports a relationship with Bayer that includes: funding grants and speaking and lecture fees. IO reports a relationship with Boston Scientific that includes: funding grants and speaking and lecture fees. IO reports a relationship with Tenaya that includes: consulting or advisory. SL reports a relationship with Takeda that includes: consulting or advisory, funding grants, and speaking and lecture fees. SL reports a relationship with Sanofi Genzyme that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. SL reports a relationship with SOBI that includes: funding grants, speaking and lecture fees, and travel reimbursement. SL reports a relationship with CLS-Behring that includes: funding grants and speaking and lecture fees. SL reports a relationship with NovoNordisk that includes: funding grants and speaking and lecture fees. SL reports a relationship with Roche that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. FP report a relationship with Biomarin International Limit that includes: board membership and speaking and lecture fees. FP report a relationship with Vitaflo that includes: travel reimbursement., (Copyright © 2022 Gorini, Santoro, Pierini, Mezzasalma, Baldacci, Bargagli, Boncristiano, Brunetto, Cameli, Cappelli, Castaman, Coco, Donati, Guerrini, Linari, Murro, Olivotto, Parronchi, Pochiero, Rossi, Scappini, Sodi, Vannucchi and Coi.)

Radiotherapy and chemotherapy represent important treatment modalities for head and neck cancer. Rhinosinusitis and smell alterations are common side effects in the sinonasal region. This review will summarize and analyze our current knowledge of the sinonasal side effects of chemotherapy and/or radiation therapy for head and neck cancer (HNC), with a specific focus on mucosal and olfactory disorders. A review of the English literature was performed using several databases (PubMed, Embase, Cochrane, Scopus). Fifty-six articles were included in qualitative synthesis: 28 assessed mucosal disorders (rhinitis or rhinosinusitis), 26 evaluated olfactory alterations, and 2 articles addressed both topics. The incidence and severity of olfactory dysfunction and chronic rhinosinusitis were highest at the end of radiotherapy and at three months after treatment and decreased gradually over time. Smell acuity deterioration and chronic rhinosinusitis seemed to be related to radiation dose on olfactory area and nasal cavities, but different degrees of recovery were observed. In conclusion, it is important to establish the severity of chronic rhinosinusitis and olfactory dysfunction in order to find strategies to support patients and improve their quality of life.

A comprehensive microscopic description of thermally induced distortions in lead halide perovskites is crucial for their realistic applications, yet still unclear. Here, we quantify the effects of thermal activation in CsPbBr 3 nanocrystals across length scales with atomic-level precision, and we provide a framework for the description of phase transitions therein, beyond the simplistic picture of unit-cell symmetry increase upon heating. The temperature increase significantly enhances the short-range structural distortions of the lead halide framework as a consequence of the phonon anharmonicity, which causes the excess free energy surface to change as a function of temperature. As a result, phase transitions can be rationalized via the soft-mode model, which also describes displacive thermal phase transitions in oxide perovskites. Our findings allow to reconcile temperature-dependent modifications of physical properties, such as changes in the optical band gap, that are incompatible with the perovskite time- and space-average structures.

Evening Primrose oil (EPO), obtained from the seeds of Evening Primrose ( Oenothera L.), is largely used as a dietary supplement, especially after cancer diagnosis. Human pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease correlated with poor clinical prognosis and a very low response rate to common chemotherapy. The aim of this work was to study the potential ability of EPO to improve the effects of chemotherapeutic drugs in PANC-1 and MIAPaCa-2 cell lines. Cytotoxicity, cell death, reactive oxygen species (ROS) production and EPO anticancer activity associated with the main chemotherapeutic drugs commonly used in therapy were investigated. Results showed that EPO reduced PDAC cell viability and increased paclitaxel efficacy. This evidence suggests that EPO may be used as a potential supplement to increase chemotherapeutic efficacy in PDAC therapy.

Background and Objective: Tuberous Sclerosis Complex (TSC) is a rare systemic disease with a high prevalence of sleep disorders (SD), although they are still largely under-recognized. The objective of this study was to assess the prevalence of SD in adult patients with TSC, and to evaluate the relationship between sleep, epilepsy, and TSC associated neuropsychiatric disorders (TAND)., Materials and Methods: We administered Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) to 114 adult patients referring to different Italian centers. We also collected information on epilepsy and TAND., Results: PSQI, ISI, and ESS revealed a positive score, respectively, in 52 (46.0%), 30 (26.5%), and 16 (14.1%) patients. PSQI was positive in 26.7% of seizure free patients versus 61.9% with active epilepsy (p = 0.003), and the association remained significative applying a multivariate logistic model considering age, antiseizure medications, TAND and nocturnal epileptic seizures (p = 0.02). ISI was positive in 3.3% of seizure free patients versus 41.3% with active epilepsy (p = 0.0004). Applying a multivariate logistic model with the independent variables listed above, the association remained significant (p = 0.007). On the other hand, multivariate logistic model considering active epilepsy as an independent variable, revealed that TAND didn't appear a significant risk factor for positive PSQI (p = 0.43) nor ISI (p = 0.09)., Conclusions: Our results confirmed that SD are highly prevalent in adults with TSC, with active epilepsy acting as a significant risk factor. A careful assessment of sleep, above all in epileptic patients, is of crucial importance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by accumulation of immature cells in bone marrow and peripheral blood. Although successful results were obtained with tyrosine kinase inhibitors, several patients showed resistance. For this reason, the identification of new strategies and therapeutic biomarkers represents an attractive goal. The role of transient receptor potential (TRP) ion channels as possible drug targets has been elucidated in different types of cancer. Among natural compounds known to activate TRPs, cannabidiol (CBD) displays anticancer properties. By using FACS analysis, confocal microscopy, gene silencing, and cell growth assay, we demonstrated that CBD, through TRPV2, inhibits cell proliferation and cell cycle in CML cells. It promoted mitochondria dysfunction and mitophagy as shown by mitochondrial mass reduction and up-regulation of several mitophagy markers. These effects were associated with changes in the expression of octamer-binding transcription factor 4 and PU.1 markers regulated during cellular differentiation. Interestingly, a synergistic effect by combining CBD with the standard drug imatinib was found and imatinib-resistant cells remain susceptible to CBD effects. Therefore, the targeting of TRPV2 by using CBD, through the activation of mitophagy and the reduction in stemness, could be a promising strategy to enhance conventional therapy and improve the prognosis of CML patients., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)